1. Field of the Invention
The invention relates generally to chemical compounds and methods for their use and preparation. In particular, the invention relates to chemical compounds having anti-mitotic activity, and the use of these compounds for treating diseases associated with abnormal cell proliferation, such as tumor.
2. Background Art
Abnormal cell proliferation disorders may include, but are not limited to, tumors, infection, immune rejection response of organ transplant, autoimmune disorders (such as arthritis, lupus, inflammatory bowel disease, Sjogrens syndrome, multiple sclerosis) or a combination thereof. Of these, tumors are perhaps the most well known. Based on the characteristics of cellular behavior, tumors can further be divided into two groups, benign and malignant tumors. Cancer also called malignant tumors can proliferate without respect to normal limits, invading and destroying adjacent tissues, and may even spread to distant anatomic sites through a process called metastasis. These life-threatening, malignant properties of tumors differentiate them from benign tumors, which are self-limited in their growth and do not invade or metastasize.
Anti-mitotic agents interfering with microtubules/tubulin dynamic equilibrium can result in the appearance of typical hallmarks at the level of chromosomes, nuclear membrane, mitotic spindle, and G2/M cells as a consequence of mitotic arrest. Several anti-mitotic agents have had considerable clinical success. For example, vinca alkaloids, such as vincristine and vinblastine, have been used to treat hematological malignancies and non-small-cell lung carcinoma. As another example, taxanes, such as paclitaxcel and docetaxel, have been successfully used to treat breast and non-small-cell lung carcinoma. Despite all these improved results to date, available anti-mitotic agents are inadequate for a number of reasons. For example, use of paclitaxcel or docetaxel can lead to neuropathy. In addition, both the vinca alkaloids and taxanes might induce tumor cells to become drug resistant cells.
There is, therefore, still a need for novel drugs in the treatment of abnormal cell proliferation. Desirable properties of powerful anti-mitotic agent include a good therapeutic index, low cytotoxicity, high bioavailability, easy of synthesis, and no drug resistance.